Quinazolinone Compounds as Anticancer Agents

ABSTRACT

Quinazolinone compounds, pharmaceutically acceptable salts, and prodrugs thereof; compositions that include a pharmaceutically acceptable carrier and one or more of the quinazolinone compounds, either alone or in combination with at least one additional therapeutic agent. Methods of using the quinazolinone compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of proliferative diseases.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional PatentApplication No. 60/525,059, filed Nov. 25, 2003.

FIELD OF THE INVENTION

The present invention relates to new quinazolinone compounds, theirpharmaceutically acceptable salts, and prodrugs thereof; compositions ofthe new compounds, either alone or in combination with at least oneadditional therapeutic agent, with a pharmaceutically acceptablecarrier; and uses of the new compounds, either alone or in combinationwith at least one additional therapeutic agent, in the prophylaxis ortreatment of proliferative diseases.

BACKGROUND OF THE INVENTION

Kinesins are motor proteins that use adenosine triphosphate to bind tomicrotubules and generate mechanical force. Kinesins are characterizedby a motor domain having about 350 amino acid residues. The crystalstructures of several kinesin motor domains have been resolved.

Currently, about one hundred kinesin-related proteins (KRP) have beenidentified. Kinesins are involved in a variety of cell biologicalprocesses including transport of organelles and vesicles, andmaintenance of the endoplasmatic reticulum. Several KRPs interact withthe microtubules of the mitotic spindle or with the chromosomesdirectly, and appear to play a pivotal role during the mitotic stages ofthe cell cycle. These mitotic KRPs are of particular interest for thedevelopment of cancer therapeutics.

Kinesin spindle protein (KSP) (also known as Eg5, HsEg5, KNSL1, orKIFII) is one of several kinesin-like motor proteins that are localizedto the mitotic spindle and known to be required for formation and/orfunction of the bipolar mitotic spindle.

In 1995, the depletion of KSP using an antibody directed against theC-terminus of KSP was shown to arrest HeLa cells in mitosis withmonoastral microtubule arrays (Blangy et al., Cell 83:1159-1169, 1995).Mutations in bimC and cut7 genes, which are considered to be homologuesof KSP, cause failure in centrosome separation in Aspergillus nidulans(Enos, A. P., and N. R. Morris, Cell 60:1019-1027, 1990) andSchizosaccharomyces pombe (Hagan, I., and M. Yanagida, Nature347:563-566, 1990). Treatment of cells with either ATRA (alltrans-retinoic acid), which reduces KSP expression on protein level, ordepletion of KSP using antisense oligonucleotides revealed a significantgrowth inhibition in DAN-G pancreatic carcinoma cells indicating thatKSP might be involved in the antiproliferative action of alltrans-retinoic acid (Kaiser, A., et al., J. Biol. Chem. 274,18925-18931, 1999). Interestingly, the Xenopus laevis Aurora-relatedprotein kinase pEg2 was shown to associate and phosphorylate X1Eg5(Giet, R., et al., J. Biol. Chem. 274:15005-15013, 1999). Potentialsubstrates of Aurora-related kinases are of particular interest forcancer drug development. For example, Aurora 1 and 2 kinases areoverexpressed on protein and RNA level and the genes are amplified incolon cancer patients.

The first cell permeable small molecule inhibitor for KSP, “monastrol,”was shown to arrest cells with monopolar spindles without affectingmicrotubule polymerization as do conventional chemotherapeutics such astaxanes and vinca alkaloids (Mayer, T. U., et al., Science 286:971-974,1999). Monastrol was identified as an inhibitor in phenotype-basedscreens and it was suggested that this compound may serve as a lead forthe development of anticancer drugs. The inhibition was determined notto be competitive in respect to adenosine triphosphate and to be rapidlyreversible (DeBonis, S., et al., Biochemistry 42:338-349, 2003; Kapoor,T. M., et al., J. Cell Biol. 150:975-988, 2000).

Recently, other KSP kinesin inhibitors have been described. WO 02/057244and WO 02/056880 describe phenothiazine compounds and triphenylmethanecompounds, respectively, for treating proliferative diseases. WO02/078639 describes cyano-substituted dihydropyrimidine compounds fortreating proliferative diseases. U.S. Pat. No. 6,472,521 describesoligonucleotides and oligonucleotide derivatives for inhibiting humanKSP expression.

WO 01/98278, WO 01/30768, and WO 03/039460 describe quinazolinonecompounds that are useful in treating cellular proliferative diseasesassociated with KSP activity. The compounds described in thesereferences are 2-(2-aminomethyl)quinazolinone derivatives. Thequinazolinone compounds described in WO 01/98278 and WO 01/30768 have2-aminomethyl substituents that are either amine, amide, or sulfonamidesubstituents. The quinazolinone compounds described in WO 03/039460 havethe amino group of the 2-aminomethyl substituent incorporated into a5-12 membered nitrogen-containing heterocycle.

WO 03/050064 describes thienopyrimidinone compounds that are useful fortreating cellular proliferative disease, for treating disordersassociated with KSP activity, and for inhibiting KSP.

WO 03/103575 describes heterocyclic-fused pyrimidinone derivatives thatare inhibitors of the mitotic KSP and that are useful in the treatmentof cellular proliferative diseases. These derivatives areN-heterocyclic-fused pyrimidinone derivatives. Representativederivatives that are described include pyrido[α,β-γ]pyrimidin-δ-ones,pyrimido[α,β-γ]pyrimidin-δ-ones, pyrimido[α,β-γ]pyridazin-δ-ones, andpteridin-4-ones.

SUMMARY OF THE INVENTION

In one aspect of the present invention, new quinazolinone compounds,their pharmaceutically acceptable salts, and prodrugs thereof areprovided. The quinazolinone compounds, pharmaceutically acceptablesalts, and prodrugs are KSP inhibitors and are useful in the treatingcellular proliferation diseases.

In one embodiment, the quinazolinone compounds have the formula (I):

a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrugthereof, wherein

X is O or S;

R₁ is selected from the group consisting of

-   -   (1) hydrogen,    -   (2) substituted or unsubstituted alkyl,    -   (3) substituted or unsubstituted alkenyl,    -   (4) substituted or unsubstituted alkynyl,    -   (5) substituted or unsubstituted aryl,    -   (6) substituted or unsubstituted heteroaryl,    -   (7) substituted or unsubstituted heterocyclyl,    -   (8) substituted or unsubstituted alkylsulfonyl, and    -   (9) substituted or unsubstituted arylsulfonyl;

R₂ is selected from the group consisting of

-   -   (1) hydrogen,    -   (2) substituted or unsubstituted alkyl,    -   (3) substituted or unsubstituted alkenyl, and    -   (4) substituted or unsubstituted alkynyl;

R₃ is selected from the group consisting of

-   -   (1) CO₂R₁₀,    -   (2) COR₁₀,    -   (3) CONR₁₁R₁₂,    -   (4) S(O)_(m)R₁₃, and    -   (5) SO₂NR₁₄R₁₅; or

R₂ and R₃ taken together with the carbon atom to which they are attachedform a 3- to 7-membered carbocyclic or heterocyclic ring;

with the proviso that when R₄ and R₅ are taken together to form a 5- to12-membered heterocyclic ring, R₃ is CONR₁₁R₁₂ or R₂ and R₃ takentogether with the carbon atom to which they are attached form a 3- to7-membered carbocyclic or heterocyclic ring;

R₄ is selected from the group consisting of

-   -   (1) hydrogen,    -   (2) substituted or unsubstituted alkyl,    -   (3) substituted or unsubstituted alkenyl,    -   (4) substituted or unsubstituted alkynyl,    -   (5) substituted or unsubstituted aryl,    -   (6) substituted or unsubstituted heteroaryl, and    -   (7) substituted or unsubstituted heterocyclyl;

R₅ is selected from the group consisting of

-   -   (1) hydrogen,    -   (2) substituted or unsubstituted alkyl,    -   (3) substituted or unsubstituted alkoxy,    -   (4) substituted or unsubstituted aryl,    -   (5) substituted or unsubstituted heteroaryl,    -   (6) substituted or unsubstituted heterocyclyl,    -   (7) COR₁₇,    -   (8) CO₂R₁₈,    -   (9) CONR₁₉R₂₀, and    -   (10) SO₂R₂₁; or

R₄ and R₅ are taken together with the nitrogen atom to which they areattached form a heteroaryl or heterocyclyl ring, wherein the heteroarylring contains one or two ring heteroatoms, wherein the heterocyclyl ringcontains one or two ring heteroatoms, and wherein the heteroaryl orheterocyclyl ring is optionally substituted with a halogen, alkyl,hydroxy, amino, cyano, alkylamino, dialkylamino, alkylaminoalkyl,dialkylaminoalkyl, alkoxy, aryl, aryloxy, heteroaryl, arylalkyl,heterocycle, aminocarbonyl, carbonylamino, alkylcarbonyl, alkylcarboxy,alkylaminocarbonyl, alkylcarbonylamino, carbocycle, or heteroarylalkylgroup; with the proviso that when R₄ and R₅ taken together with thenitrogen atom to which they are attached form a 5-membered heterocyclicring, the heterocyclic ring is not a 2,4-dioxo-3-oxazolidinyl ring, a2,5-dioxo-1-imidazolidinyl ring, or a 2,4,5-trioxo-1-imidazolidinylring;

R₆, R₇, R₈, and R₉ are independently selected from the group consistingof

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxy,    -   (4) nitro,    -   (5) amino,    -   (6) cyano,    -   (7) alkoxy,    -   (8) alkylthio,    -   (9) methylenedioxy,    -   (10) haloalkoxy,    -   (11) CO₂R₁₀,    -   (12) COR₁₀,    -   (13) OR₁₀,    -   (14) CONR₁₁R₁₂,    -   (15) substituted or unsubstituted alkyl,    -   (16) substituted or unsubstituted aryl,    -   (17) substituted or unsubstituted heteroaryl,    -   (18) substituted or unsubstituted alkylamino,    -   (19) substituted or unsubstituted dialkylamino,    -   (20) substituted or unsubstituted alkylsulfonyl,    -   (21) substituted or unsubstituted arylsulfonyl,    -   (22) substituted or unsubstituted alkylcarboxy,    -   (23) substituted or unsubstituted carboxamido,    -   (24) substituted or unsubstituted carboxyamino,    -   (25) substituted or unsubstituted aminocarboxy,    -   (26) substituted or unsubstituted aminocarbonyl, and    -   (27) substituted or unsubstituted alkylsulfonamido;

R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₇, R₁₈, R₁₉, R₂₀, and R₂₁ areindependently selected from the group consisting of

-   -   (1) hydrogen,    -   (2) substituted or unsubstituted alkyl,    -   (3) substituted or unsubstituted alkenyl,    -   (4) substituted or unsubstituted alkynyl,    -   (5) substituted or unsubstituted aryl,    -   (6) substituted or unsubstituted heteroaryl, and    -   (7) substituted or unsubstituted heterocyclyl; or

R₁₁ and R₁₂, R₁₄ and R₁₅, or R₁₉ and R₂₀ taken together form a 3- to7-membered carbocyclic or heterocyclic ring; and

m=0, 1, or 2.

In another aspect, the present invention provides methods for treatingproliferative diseases in a human or animal subject in need of suchtreatment comprising administering to said subject an amount of acompound of formula (I) effective to reduce or prevent cellularproliferation in the subject.

In another aspect of the present invention, methods for treatingproliferative diseases in a human or animal subject in need of suchtreatment, comprising administering to said subject an amount of acompound of formula (I) effective to reduce or prevent cellularproliferation in the subject in combination with at least one additionalagent for the treatment of cancer.

In other aspects, the present invention provides therapeuticcompositions, comprising at least one compound of formula (I) incombination with one or more additional agents for the treatment ofcancer, as are commonly employed in cancer therapy.

The compounds of the invention are useful in the treatment of cancers,including, for example, lung and bronchus; prostate; breast; pancreas;colon and rectum; thyroid; stomach; liver and intrahepatic bile duct;kidney and renal pelvis; urinary bladder; uterine corpus; uterinecervix; ovary; multiple myeloma; esophagus; acute myelogenous leukemia;chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia;brain; oral cavity and pharynx; larynx; small intestine; non-hodgkinlymphoma; melanoma; and villous colon adenoma.

The invention further provides compositions, kits, methods of use, andmethods of manufacture as described in the detailed description of theinvention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

In one aspect of the present invention, new quinazolinone compounds,their pharmaceutically acceptable salts, and prodrugs thereof areprovided. The quinazolinone compounds, pharmaceutically acceptablesalts, and prodrugs are KSP inhibitors and are useful in the treatingcellular proliferation diseases.

The quinazolinone compounds have the formula (I):

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orprodrug thereof, wherein

X is O or S;

R₁ is selected from the group consisting of

-   -   (1) hydrogen,    -   (2) substituted or unsubstituted alkyl,    -   (3) substituted or unsubstituted alkenyl,    -   (4) substituted or unsubstituted alkynyl,    -   (5) substituted or unsubstituted aryl,    -   (6) substituted or unsubstituted heteroaryl,    -   (7) substituted or unsubstituted heterocyclyl,    -   (8) substituted or unsubstituted alkylsulfonyl, and    -   (9) substituted or unsubstituted arylsulfonyl;

R₂ is selected from the group consisting of

-   -   (1) hydrogen,    -   (2) substituted or unsubstituted alkyl,    -   (3) substituted or unsubstituted alkenyl, and    -   (4) substituted or unsubstituted alkynyl;

R₃ is selected from the group consisting of

-   -   (1) CO₂R₁₀,    -   (2) COR₁₀,    -   (3) CONR₁₁R₁₂,    -   (4) S(O)_(m)R₁₃, and    -   (5) SO₂NR₁₄R₁₅; or

R₂ and R₃ taken together with the carbon atom to which they are attachedform a 3- to 7-membered carbocyclic or heterocyclic ring;

with the proviso that when R₄ and R₅ are taken together to form a 5- to12-membered heterocyclic ring, R₃ is CONR₁₁R₁₂ or R₂ and R₃ takentogether with the carbon atom to which they are attached form a 3- to7-membered carbocyclic or heterocyclic ring;

R₄ is selected from the group consisting of

-   -   (1) hydrogen,    -   (2) substituted or unsubstituted alkyl,    -   (3) substituted or unsubstituted alkenyl,    -   (4) substituted or unsubstituted alkynyl,    -   (5) substituted or unsubstituted aryl,    -   (6) substituted or unsubstituted heteroaryl, and    -   (7) substituted or unsubstituted heterocyclyl;

R₅ is selected from the group consisting of

-   -   (1) hydrogen,    -   (2) substituted or unsubstituted alkyl,    -   (3) substituted or unsubstituted alkoxy,    -   (4) substituted or unsubstituted aryl,    -   (5) substituted or unsubstituted heteroaryl,    -   (6) substituted or unsubstituted heterocyclyl,    -   (7) COR₁₇,    -   (8) CO₂R₁₈,    -   (9) CONR₁₉R₂₀, and    -   (10) SO₂R₂₁; or

R₄ and R₅ are taken together with the nitrogen atom to which they areattached form a heteroaryl or heterocyclyl ring, wherein the heteroarylring contains one or two ring heteroatoms, wherein the heterocyclyl ringcontains one or two ring heteroatoms, and wherein the heteroaryl orheterocyclyl ring is optionally substituted with a halogen, alkyl,hydroxy, amino, cyano, alkylamino, dialkylamino, alkylaminoalkyl,dialkylaminoalkyl, alkoxy, aryl, aryloxy, heteroaryl, arylalkyl,heterocycle, aminocarbonyl, carbonylamino, alkylcarbonyl, alkylcarboxy,alkylaminocarbonyl, alkylcarbonylamino, carbocycle, or heteroarylalkylgroup; with the proviso that when R₄ and R₅ taken together with thenitrogen atom to which they are attached form a 5-membered heterocyclicring, the heterocyclic ring is not a 2,4-dioxo-3-oxazolidinyl ring, a2,5-dioxo-1-imidazolidinyl ring, or a 2,4,5-trioxo-1-imidazolidinylring;

R₆, R₇, R₉, and R₉ are independently selected from the group consistingof

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxy,    -   (4) nitro,    -   (5) amino,    -   (6) cyano,    -   (7) alkoxy,    -   (8) alkylthio,    -   (9) methylenedioxy,    -   (10) haloalkoxy,    -   (11) CO₂R₁₀,    -   (12) COR₁₀,    -   (13) OR₁₀,    -   (14) CONR₁₁R₁₂,    -   (15) substituted or unsubstituted alkyl,    -   (16) substituted or unsubstituted aryl,    -   (17) substituted or unsubstituted heteroaryl,    -   (18) substituted or unsubstituted alkylamino,    -   (19) substituted or unsubstituted dialkylamino,    -   (20) substituted or unsubstituted alkylsulfonyl,    -   (21) substituted or unsubstituted arylsulfonyl,    -   (22) substituted or unsubstituted alkylcarboxy,    -   (23) substituted or unsubstituted carboxamido,    -   (24) substituted or unsubstituted carboxyamino,    -   (25) substituted or unsubstituted aminocarboxy,    -   (26) substituted or unsubstituted aminocarbonyl, and    -   (27) substituted or unsubstituted alkylsulfonamido;

R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₇, R₁₈, R₁₉, R₂₀, and R₂₁ areindependently selected from the group consisting of

-   -   (1) hydrogen,    -   (2) substituted or unsubstituted alkyl,    -   (3) substituted or unsubstituted alkenyl,    -   (4) substituted or unsubstituted alkynyl,    -   (5) substituted or unsubstituted aryl,    -   (6) substituted or unsubstituted heteroaryl, and    -   (7) substituted or unsubstituted heterocyclyl; or

R₁₁ and R₁₂, R₁₄ and R₁₅, or R₁₉ and R₂₀ taken together form a 3- to7-membered carbocyclic or heterocyclic ring; and

m=0, 1, or 2.

In one embodiment, X is O.

In one embodiment, R₁ is arylalkyl. In one embodiment, the arylalkyl isbenzyl or substituted benzyl. In one embodiment, R₁ is ahalo-substituted benzyl. In one embodiment, R₁ is 3-chlorobenzyl. In oneembodiment, R₁ is 3-fluorobenzyl. In one embodiment, R₁ is3-methoxybenzyl. In one embodiment, R₁ is 3-trifluoromethylbenzyl. Inone embodiment, R₁ is 3-trifluoromethoxybenzyl. In one embodiment, R₁ is3,5-dimethylbenzyl. In one embodiment, R₁ is 2-naphthylmethyl.

In one embodiment, R₂ is hydrogen and R₃ is CO₂R₁₀. In one embodiment,R₁₀ is alkyl.

In one embodiment, R₂ is hydrogen and R₃ is CONR₁₁R₁₂. In oneembodiment, R₁₁ and R₁₂ are alkyl. In one embodiment, R₁₁ and R₁₂ aremethyl. In one embodiment, R₁₁ and R₁₂ are taken together to with thenitrogen atom to which they are attached from a 3- to 7-memberedheterocyclic ring.

In one embodiment, R₄ is amino-substituted alkyl. In one embodiment, R₄is 3-aminopropyl.

In one embodiment, R₅ is hydrogen, alkyl, aryl, or COR₁₇. In oneembodiment, R₁₇ is aryl, arylalkyl, alkyl-substituted aryl, orhalogen-substituted aryl.

In one embodiment, R₆, R₈, and R₉ are hydrogen.

In one embodiment, R₇ is a halogen.

For the compounds of formula (I), representative substituted alkylgroups include arylalkyl, heteroarylalkyl, heterocyclyalkyl, aminoalkyl,alkylaminoalkyl, dialkyaminoalkyl, and sulfonamidoalkyl groups.Representative substituted aryl groups include sulfonamidoaryl groups.Representative substituted heteroaryl groups include alkylheteroarylgroups.

In other aspects, the present invention provides methods for manufactureof compounds of formula (I). Methods of making representative compoundsof the invention are described in Examples 1 and 2. It is furthercontemplated that, in addition to the compounds of formula (I),intermediates and their corresponding methods of syntheses are includedwithin the scope of the invention. Representative compounds of theinvention are illustrated in Table 1 in Example 3.

In other aspects, the present invention provides compositions thatinclude the KSP inhibitors described herein, and methods that utilizethe KSP inhibitors described herein.

In one aspect, the present invention provides pharmaceuticalcompositions comprising at least one quinazolinone compound (e.g., acompound of formula (I)) together with a pharmaceutically acceptablecarrier suitable for administration to a human or animal subject, eitheralone or together with other anticancer agents.

A number of suitable anticancer agents to be used as combinationtherapeutics are contemplated for use in the compositions and methods ofthe present invention. Suitable anticancer agents to be used incombination with the compounds of the invention include agents thatinduce apoptosis; polynucleotides (e.g., ribozymes); polypeptides (e.g.,enzymes); drugs; biological mimetics; alkaloids; alkylating agents;antitumor antibiotics; antimetabolites; hormones; platinum compounds;monoclonal antibodies conjugated with anticancer drugs, toxins, and/orradionuclides; biological response modifiers (e.g., interferons [e.g.,IFN-a] and interleukins [e.g., IL-2]); adoptive immunotherapy agents;hematopoietic growth factors; agents that induce tumor celldifferentiation (e.g., all-trans-retinoic acid); gene therapy reagents;antisense therapy reagents and nucleotides; tumor vaccines; inhibitorsof angiogenesis, and the like. Numerous other examples ofchemotherapeutic compounds and anticancer therapies suitable forcoadministration with the disclosed compounds of formula (I) are knownto those skilled in the art.

In certain embodiments, anticancer agents to be used in combination withcompounds of the present invention comprise agents that induce orstimulate apoptosis. Agents that induce apoptosis include, but are notlimited to, radiation; kinase inhibitors (e.g., Epidermal Growth FactorReceptor [EGFR] kinase inhibitor, Vascular Growth Factor Receptor [VGFR]kinase inhibitor, Fibroblast Growth Factor Receptor [FGFR] kinaseinhibitor, Platelet-derived Growth Factor Receptor [PGFR] I kinaseinhibitor, and Bcr-Abl kinase inhibitors such as STI-571, Gleevec, andGlivec]); antisense molecules; antibodies [e.g., Herceptin and Rituxan];anti-estrogens [e.g., raloxifene and tamoxifen]; anti-androgens [e.g.,flutamide, bicalutamide, finasteride, amino-glutethamide, ketoconazole,and corticosteroids]; cyclooxygenase 2 (COX-2) inhibitors [e.g.,Celecoxib, meloxicam, NS-398, and non-steroidal anti-inflammatory drugs(NSAIDs)]; and cancer chemotherapeutic drugs [e.g., irinotecan(Camptosar), CPT-11, fludarabine (Fludara), dacarbazine (DTIC),dexamethasone, mitoxantrone, Mylotarg, VP-16, cisplatinum, 5-FU,Doxrubicin, TAXOTERE or TAXOL]; cellular signaling molecules; ceramidesand cytokines; and staurosprine; and the like.

In other aspects, the invention provides methods for using the compoundsdescribed herein. For example, the compounds described herein can beused in the treatment of cancer. The compounds described herein can alsobe used in the manufacture of a medicament for the treatment of cancer.

In one embodiment, the present invention provides methods of treatinghuman or animal subjects suffering from a cellular proliferativedisease, such as cancer. The present invention provides methods oftreating a human or animal subject in need of such treatment, comprisingadministering to the subject a therapeutically effective amount of anquinazolinone compound (e.g., a compound of formula (I)), either aloneor in combination with other anticancer agents.

In another embodiment, the present invention provides methods fortreating a cellular proliferative disease in a human or animal subjectin need of such treatment comprising, administering to said subject anamount of an quinazolinone compound (e.g., a compound of formula (I))effective to reduce or prevent cellular proliferation or tumor growth inthe subject.

In another embodiment, the present invention provides methods fortreating a cellular proliferative disease in a human or animal subjectin need of such treatment comprising administering to said subject anamount of an quinazolinone compound (e.g., a compound of formula (I))effective to reduce or prevent cellular proliferation in the subject incombination with at least one additional agent for the treatment ofcancer.

The present invention provides compounds that are inhibitors of KSP. Theinhibitors are useful in pharmaceutical compositions for human orveterinary use where inhibition of KSP is indicated, e.g., in thetreatment of cellular proliferative diseases such as tumor and/orcancerous cell growth mediated by KSP. In particular, the compounds areuseful in the treatment of human or animal (e.g., murine) cancers,including, for example, lung and bronchus; prostate; breast; pancreas;colon and rectum; thyroid; stomach; liver and intrahepatic bile duct;kidney and renal pelvis; urinary bladder; uterine corpus; uterinecervix; ovary; multiple myeloma; esophagus; acute myelogenous leukemia;chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia;brain; oral cavity and pharynx; larynx; small intestine; non-hodgkinlymphoma; melanoma; and villous colon adenoma.

In another embodiment, the invention provides methods of treating an KSPmediated disorder. In one method, an effective amount of anquinazolinone compound is administered to a patient (e.g., a human oranimal subject) in need thereof to mediate (or modulate) KSP activity.

A representative assay for determining KSP inhibitory activity isdescribed in Example 4.

The following definitions are provided to better understand theinvention.

As used herein, the term “quinazolinone” refers to a quinazolinonecompound having a carbonyl or thiocarbonyl group at position 4.

“Alkyl” refers to alkyl groups that do not contain heteroatoms. Thus thephrase includes straight chain alkyl groups such as methyl, ethyl,propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl,dodecyl and the like. The phrase also includes branched chain isomers ofstraight chain alkyl groups, including but not limited to, the followingwhich are provided by way of example: —CH(CH₃)₂, —CH(CH₃)(CH₂CH₃),—CH(CH₂CH₃)₂, —C(CH₃)₃, —C(CH₂CH₃)₃, —CH₂CH(CH₃)₂, —CH₂CH(CH₃)(CH₂CH₃),—CH₂CH(CH₂CH₃)₂, —CH₂C(CH₃)₃, —CH₂C(CH₂CH₃)₃, —CH(CH₃)—CH(CH₃)(CH₂CH₃),—CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH(CH₃)(CH₂CH₃), —CH₂CH₂CH(CH₂CH₃)₂,—CH₂CH₂C(CH₃)₃, —CH₂CH₂C(CH₂CH₃)₃, —CH(CH₃)CH₂₋CH(CH₃)₂,—CH(CH₃)CH(CH₃)CH(CH₃)₂, —CH(CH₂CH₃)CH(CH₃)CH(CH₃)(CH₂CH₃), and others.The phrase also includes cyclic alkyl groups such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl andsuch rings substituted with straight and branched chain alkyl groups asdefined above. Thus the phrase “alkyl groups” includes primary alkylgroups, secondary alkyl groups, and tertiary alkyl groups. Preferredalkyl groups include straight and branched chain alkyl groups and cyclicalkyl groups having 1 to 12 carbon atoms.

“Alkylene” refers to the same residues as noted above for “alkyl,” buthaving two points of attachment. Exemplary alkylene groups includeethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—), dimethylpropylene(—CH₂C(CH₃)₂CH₂—), and cyclohexylpropylene (—CH₂CH₂CH(C₆H₁₃)—).

“Alkenyl” refers to straight chain, branched, or cyclic radicals havingone or more carbon-carbon double bonds and from 2 to about 20 carbonatoms. Preferred alkenyl groups include straight chain and branchedalkenyl groups and cyclic alkenyl groups having 2 to 12 carbon atoms.

“Alkynyl” refers to straight chain, branched, or cyclic radicals havingone or more carbon-carbon triple bonds and from 2 to about 20 carbonatoms. Preferred alkynyl groups include straight chain and branchedalkynyl groups having 2 to 12 carbon atoms.

Alkyl, alkenyl, and alkynyl groups may be substituted. “Substitutedalkyl” refers to an alkyl group as defined above in which one or morebonds to a carbon(s) or hydrogen(s) are replaced by a bond tonon-hydrogen and non-carbon atoms such as, but not limited to, a halogenatom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxylgroups, alkoxy groups, aryloxy groups, and ester groups; a sulfur atomin groups such as thiol groups, alkyl and aryl sulfide groups, sulfonegroups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groupssuch as amines, amides, alkylamines, dialkylamines, arylamines,alkylarylamines, diarylamines, N-oxides, imides, and enamines; a siliconatom in groups such as in trialkylsilyl groups, dialkylarylsilyl groups,alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatomsin various other groups. Substituted alkyl groups also include groups inwhich one or more bonds to a carbon(s) or hydrogen(s) atom is replacedby a higher-order bond (e.g., a double- or triple-bond) to a heteroatomsuch as oxygen in oxo, carbonyl, carboxyl, and ester groups; nitrogen ingroups such as imines, oximes, hydrazones, and nitriles. Substitutedalkyl groups further include alkyl groups in which one or more bonds toa carbon(s) or hydrogen(s) atoms is replaced by a bond to an aryl,heteroaryl, heterocyclyl, or cycloalkyl group. Preferred substitutedalkyl groups include, among others, alkyl groups in which one or morebonds to a carbon or hydrogen atom is/are replaced by one or more bondsto fluoro, chloro, or bromo group. Another preferred substituted alkylgroup is the trifluoromethyl group and other alkyl groups that containthe trifluoromethyl group. Other preferred substituted alkyl groupsinclude those in which one or more bonds to a carbon or hydrogen atom isreplaced by a bond to an oxygen atom such that the substituted alkylgroup contains a hydroxyl, alkoxy, or aryloxy group. Other preferredsubstituted alkyl groups include alkyl groups that have an amine, or asubstituted or unsubstituted alkylamine, dialkylamine, arylamine,(alkyl)(aryl)amine, diarylamine, heterocyclylamine, diheterocyclylamine,(alkyl)(heterocyclyl)amine, or (aryl)(heterocyclyl)amine group. Stillother preferred substituted alkyl groups include those in which one ormore bonds to a carbon(s) or hydrogen(s) atoms is replaced by a bond toan aryl, heteroaryl, heterocyclyl, or cycloalkyl group. Examples ofsubstituted alkyl are: —(CH₂)₃NH₂, —(CH₂)₃NH(CH₃), —(CH₂)₃NH(CH₃)₂,—CH₂C(═CH₂)CH₂NH₂, —CH₂C(═O)CH₂NH₂, —CH₂S(═O)₂CH₃, —CH₂OCH₂NH₂, —CO₂H.Examples of substituents of substituted alkyl are: —CH₃, —C₂H₅, —CH₂OH,—OH, —OCH₃, —OC₂H₅, —OCF₃, —OC(═O)CH₃, —OC(═O)NH₂, —OC(═O)N(CH₃)₂, —CN,—NO₂, —C(═O)CH₃, —CO₂H, —CO₂CH₃, —CONH₂, —NH₂, —N(CH₃)₂, —NHSO₂CH₃,—NHCOCH₃, —NHC(═O)OCH₃, —NHSO—₂CH₃, —SO₂CH₃, —SO₂NH₂, Halo.

“Substituted alkenyl” has the same meaning with respect to alkenylgroups that substituted alkyl groups had with respect to unsubstitutedalkyl groups. A substituted alkenyl group includes alkenyl groups inwhich a non-carbon or non-hydrogen atom is bonded to a carbon doublebonded to another carbon and those in which one of the non-carbon ornon-hydrogen atoms is bonded to a carbon not involved in a double bondto another carbon.

“Substituted alkynyl” has the same meaning with respect to alkynylgroups that substituted alkyl groups had with respect to unsubstitutedalkyl groups. A substituted alkynyl group includes alkynyl groups inwhich a non-carbon or non-hydrogen atom is bonded to a carbon triplebonded to another carbon and those in which a non-carbon or non-hydrogenatom is bonded to a carbon not involved in a triple bond to anothercarbon.

“Alkoxy” refers to RO— wherein R is alkyl. Representative examples ofalkoxy groups include methoxy, ethoxy, t-butoxy, trifluoromethoxy, andthe like.

“Halogen” or “halo” refers to chloro, bromo, fluoro, and iodo groups.The term “haloalkyl” refers to an alkyl radical substituted with one ormore halogen atoms. The term “haloalkoxy” refers to an alkoxy radicalsubstituted with one or more halogen atoms.

“Amino” refers herein to the group —NH₂. The term “alkylamino” refersherein to the group —NRR′ where R is alkyl and R′ is hydrogen or alkyl.The term “arylamino” refers herein to the group —NRR′ where R is aryland R′ is hydrogen, alkyl, or aryl. The term “aralkylamino” refersherein to the group —NRR′ where R is aralkyl and R′ is hydrogen, alkyl,aryl, or aralkyl.

“Alkoxyalkyl” refers to the group -alk₁-O-alk₂ where alk₁ is alkyl oralkenyl, and alk₂ is alkyl or alkenyl. The term “aryloxyalkyl” refers tothe group -alkyl O-aryl. The term “aralkoxyalkyl” refers to the group-alkylenyl-O-aralkyl.

“Alkoxyalkylamino” refers herein to the group —NR-(alkoxyalkyl), where Ris typically hydrogen, aralkyl, or alkyl.

“Aminocarbonyl” refers herein to the group —C(O)—NH₂. “Substitutedaminocarbonyl” refers herein to the group —C(O)—NRR′ where R is alkyland R′ is hydrogen or alkyl. The term “arylaminocarbonyl” refers hereinto the group —C(O)—NRR′ where R is aryl and R′ is hydrogen, alkyl oraryl. “Aralkylaminocarbonyl” refers herein to the group —C(O)—NRR′ whereR is aralkyl and R′ is hydrogen, alkyl, aryl, or aralkyl.

“Aminosulfonyl” refers herein to the group —S(O)₂—NH₂. “Substitutedaminosulfonyl” refers herein to the group —S(O)₂—NRR′ where R is alkyland R′ is hydrogen or alkyl. The term “aralkylaminosulfonlyaryl” refersherein to the group -aryl-S(O)₂—NH-aralkyl.

“Carbonyl” refers to the divalent group —C(O)—.

“Carbonyloxy” refers generally to the group —C(O)—O, Such groups includeesters, —C(O)—O—R, where R is alkyl, cycloalkyl, aryl, or aralkyl. Theterm “carbonyloxycycloalkyl” refers generally herein to both a“carbonyloxycarbocycloalkyl” and a “carbonyloxyheterocycloalkyl,” i.e.,where R is a carbocycloalkyl or heterocycloalkyl, respectively. The term“arylcarbonyloxy” refers herein to the group —C(O)—O-aryl, where aryl isa mono- or polycyclic, carbocycloaryl or heterocycloaryl. The term“aralkylcarbonyloxy” refers herein to the group —C(O)—O-aralkyl.

“Sulfonyl” refers herein to the group —SO₂—. “Alkylsulfonyl” refers to asubstituted sulfonyl of the structure —SO₂R— in which R is alkyl.Alkylsulfonyl groups employed in compounds of the present invention aretypically alkylsulfonyl groups having from 1 to 6 carbon atoms in itsbackbone structure. Thus, typical alkylsulfonyl groups employed incompounds of the present invention include, for example, methylsulfonyl(i.e., where R is methyl), ethylsulfonyl (i.e., where R is ethyl),propylsulfonyl (i.e., where R is propyl), and the like. The term“arylsulfonyl” refers herein to the group —SO₂-aryl. The term“aralkylsulfonyl” refers herein to the group —SO₂-aralkyl. The term“sulfonamido” refers herein to —SO₂NH₂.

“Carbonylamino” refers to the divalent group —NH—C(O)— in which thehydrogen atom of the amide nitrogen of the carbonylamino group can bereplaced alkyl, aryl, or aralkyl group. Such groups include moietiessuch as carbamate esters (—NH—C(O)—O—R) and amides —NH—C(O)—R, where Ris a straight or branched chain alkyl, cycloalkyl, or aryl or aralkyl.The term “alkylcarbonylamino” refers to alkylcarbonylamino where R isalkyl having from 1 to about 6 carbon atoms in its backbone structure.The term “arylcarbonylamino” refers to group —NH—C(O)—R where R is anaryl. Similarly, the term “aralkylcarbonylamino” refers to carbonylaminowhere R is aralkyl.

“Guanidino” or “guanidyl” refers to moieties derived from guanidine,H₂N—C(═NH)—NH₂. Such moieties include those bonded at the nitrogen atomcarrying the formal double bond (the “2”-position of the guanidine,e.g., diaminomethyleneamino, (H₂N)₂C═NH—)) and those bonded at either ofthe nitrogen atoms carrying a formal single bond (the “1-” and/or“3”-positions of the guandine, e.g., H₂N—C(═NH)—NH—)). The hydrogenatoms at any of the nitrogens can be replaced with a suitablesubstituent, such as alkyl, aryl, or aralkyl.

“Amidino” refers to the moieties R—C(═N)—NR′— (the radical being at the“N¹” nitrogen) and R(NR′)C═N— (the radical being at the “N²” nitrogen),where R and R′ can be hydrogen, alkyl, aryl, or aralkyl.

“Cycloalkyl” refers to a mono- or polycyclic, heterocyclic orcarbocyclic alkyl substituent. Typical cycloalkyl substituents have from3 to 8 backbone (i.e., ring) atoms in which each backbone atom is eithercarbon or a heteroatom. The term “heterocycloalkyl” refers herein tocycloalkyl substituents that have from 1 to 5, and more typically from 1to 4 heteroatoms in the ring structure. Suitable heteroatoms employed incompounds of the present invention are nitrogen, oxygen, and sulfur.Representative heterocycloalkyl moieties include, for example,morpholino, piperazinyl, piperadinyl, and the like. Carbocycloalkylgroups are cycloalkyl groups in which all ring atoms are carbon. Whenused in connection with cycloalkyl substituents, the term “polycyclic”refers herein to fused and non-fused alkyl cyclic structures.

“Substituted heterocycle,” “heterocyclic group,” “heterocycle,” or“heterocyclyl,” as used herein refers to any 3- or 4-membered ringcontaining a heteroatom selected from nitrogen, oxygen, and sulfur or a5- or 6-membered ring containing from one to three heteroatoms selectedfrom the group consisting of nitrogen, oxygen, or sulfur; wherein the5-membered ring has 0-2 double bonds and the 6-membered ring has 0-3double bonds; wherein the nitrogen and sulfur atom maybe optionallyoxidized; wherein the nitrogen and sulfur heteroatoms maybe optionallyquarternized; and including any bicyclic group in which any of the aboveheterocyclic rings is fused to a benzene ring or another 5- or6-membered heterocyclic ring independently defined above. The term“heterocycle” thus includes rings in which nitrogen is the heteroatom aswell as partially and fully-saturated rings. Preferred heterocyclesinclude, for example: diazapinyl, pyrryl, pyrrolinyl, pyrrolidinyl,pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazoyl, imidazolinyl,imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, N-methylpiper-azinyl, azetidinyl, N-methylazetidinyl, pyrimidinyl, pyridazinyl,oxazolyl, oxazolidinyl, isoxazolyl, isoazolidinyl, morpholinyl,thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl,quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl,furyl, thienyl, triazolyl, and benzothienyl.

Heterocyclic moieties can be unsubstituted or monosubstituted ordisubstituted with various substituents independently selected fromhydroxy, halo, oxo (C═O), alkylimino (RN═, wherein R is alkyl or alkoxygroup), amino, alkylamino, dialkylamino, acylaminoalkyl, alkoxy,thioalkoxy, polyalkoxy, alkyl, cycloalkyl or haloalkyl.

The heterocyclic groups may be attached at various positions as will beapparent to those having skill in the organic and medicinal chemistryarts in conjunction with the disclosure herein.

where R is H or a heterocyclic substituent, as described herein.

Representative heterocyclics include, for example, imidazolyl, pyridyl,piperazinyl, azetidinyl, thiazolyl, furanyl, triazolyl benzimidazolyl,benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, indolyl, naphthpyridinyl, indazolyl, andquinolizinyl.

“Aryl” refers to optionally substituted monocyclic and polycyclicaromatic groups having from 3 to 14 backbone carbon or hetero atoms, andincludes both carbocyclic aryl groups and heterocyclic aryl groups.Carbocyclic aryl groups are aryl groups in which all ring atoms in thearomatic ring are carbon. The term “heteroaryl” refers herein to arylgroups having from 1 to 4 heteroatoms as ring atoms in an aromatic ringwith the remainder of the ring atoms being carbon atoms. When used inconnection with aryl substituents, the term “polycyclic aryl” refersherein to fused and non-fused cyclic structures in which at least onecyclic structure is aromatic, such as, for example, benzodioxozolo(which has a heterocyclic structure fused to a phenyl group, i.e.,

naphthyl, and the like. Exemplary aryl moieties employed as substituentsin compounds of the present invention include phenyl, pyridyl,pyrimidinyl, thiazolyl, indolyl, imidazolyl, oxadiazolyl, tetrazolyl,pyrazinyl, triazolyl, thiophenyl, furanyl, quinolinyl, purinyl,naphthyl, benzothiazolyl, benzopyridyl, and benzimidazolyl, and thelike.

“Aralkyl” or “arylalkyl” refers to an alkyl group substituted with anaryl group. Typically, aralkyl groups employed in compounds of thepresent invention have from 1 to 6 carbon atoms incorporated within thealkyl portion of the aralkyl group. Suitable aralkyl groups employed incompounds of the present invention include, for example, benzyl,picolyl, and the like.

Representative heteroaryl groups include, for example, those shownbelow. These heteroaryl groups can be further substituted and may beattached at various positions as will be apparent to those having skillin the organic and medicinal chemistry arts in conjunction with thedisclosure herein.

Representative heteroaryls include, for example, imidazolyl, pyridyl,thiazolyl, triazolyl benzimidazolyl, benzothiazolyl, and benzoxazolyl.

“Biaryl” refers to a group or substituent to which two aryl groups,which are not condensed to each other, are bound. Exemplary biarylcompounds include, for example, phenylbenzene, diphenyldiazene,4-methylthio-1-phenylbenzene, phenoxybenzene, (2-phenylethynyl)benzene,diphenyl ketone, (4-phenylbuta-1,3-diynyl)benzene, phenylbenzylamine,(phenylmethoxy)benzene, and the like. Preferred optionally substitutedbiaryl groups include:2-(phenylamino)-N-[4-(2-phenylethynyl)-phenyl]acetamide,1,4-diphenylbenzene,N-[4-(2-phenylethynyl)phenyl]-2-[benzyl-amino]-acetamide,2-amino-N-[4-(2-phenylethynyl)phenyl]propanamide,2-amino-N-[4-(2-phenyl-ethynyl)phenyl]acetamide,2-(cyclopropylamino)-N-[4-(2-phenylethynyl)-phenyl]-acetamide,2-(ethylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide,2-[(2-methyl-propyl)amino]-N-[4-(2-phenylethynyl)phenyl]acetamide,5-phenyl-2H-benzo-[d]1,3-dioxolene, 2-chloro-1-methoxy-4-phenylbenzene,2-[(imidazolylmethyl)-amino]-N-[4-(2-phenylethynyl)phenyl]acetamide,4-phenyl-1-phenoxybenzene,N-(2-amino-ethyl)-[4-(2-phenylethynyl)phenyl]carboxamide,2-{[(4-fluorophenyl)methyl]-amino}-N-[4-(2-phenylethynyl)phenyl]acetamide,2-{[(4-methylphenyl)methyl]amino}-N-[4-(2-phenyl-ethynyl)phenyl]acetamide,4-phenyl-1-(trifluoromethyl)benzene, 1-butyl-4-phenyl-benzene,2-(cyclohexylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide,2-(ethyl-methyl-amino)-N-[4-(2-phenylethynyl)phenyl]acetamide,2-(butylamino)-N-[4-(2-phenyl-ethynyl)-phenyl]acetamide,N-[4-(2-phenylethynyl)phenyl]-2-(4-pyridylamino)-acetamide,N-[4-(2-phenylethynyl)phenyl]-2-(quinuclidin-3-ylamino)acetamide,N-[4-(2-phenyl-ethynyl)phenyl]pyrrolidin-2-ylcarboxamide,2-amino-3-methyl-N-[4-(2-phenyl-ethynyl)-phenyl]butanamide,4-(4-phenylbuta-1,3-diynyl)phenylamine,2-(dimethyl-amino)-N-[4-(4-phenylbuta-1,3-diynyl)phenyl]acetamide,2-(ethylamino)-N-[4-(4-phenylbuta-1,3-diynyl)-phenyl]acetamide,4-ethyl-1-phenylbenzene, 1-[4-(2-phenyl-ethynyl)-phenyl]ethan-1-one,N-(1-carbamoyl-2-hydroxypropyl)[4-(4-phenylbuta-1,3-diynyl)-phenyl]-carbox-amide,N-[4-(2-phenylethynyl)phenyl]propanamide, 4-methoxy-phenyl phenylketone, phenyl-N-benzamide,(tert-butoxy)-N-[(4-phenylphenyl)-methyl]-carboxamide,2-(3-phenyl-phenoxy)ethanehydroxamic acid, 3-phenylphenyl propanoate,1-(4-ethoxyphenyl)-4-methoxybenzene, and[4-(2-phenylethynyl)phenyl]pyrrole.

“Heteroarylaryl” refers to a biaryl group where one of the aryl groupsis a heteroaryl group. Exemplary heteroarylaryl groups include, forexample, 2-phenylpyridine, phenylpyrrole, 3-(2-phenylethynyl)pyridine,phenylpyrazole, 5-(2-phenyl-ethynyl)-1,3-dihydropyrimidine-2,4-dione,4-phenyl-1,2,3-thiadiazole, 2-(2-phenyl-ethynyl)pyrazine,2-phenylthiophene, phenylimidazole, 3-(2-piperazinyl-phenyl)-furan,3-(2,4-dichlorophenyl)-4-methylpyrrole, and the like. Preferredoptionally substituted heteroarylaryl groups include:5-(2-phenylethynyl)pyrimidine-2-ylamine, 1-methoxy-4-(2-thienyl)benzene,1-methoxy-3-(2-thienyl)benzene, 5-methyl-2-phenyl-pyridine,5-methyl-3-phenylisoxazole, 2-[3-(trifluoromethyl)phenyl]furan,3-fluoro-5-(2-furyl)-2-methoxy-1-prop-2-enylbenzene,(hydroxyimino)(5-phenyl(2-thienyl))-methane,5-[(4-methylpiperazinyl)methyl]-2-phenylthiophene,2-(4-ethylphenyl)-thiophene, 4-methyl-thio-1-(2-thienyl)benzene,2-(3-nitrophenyl)thiophene,(tert-butoxy)-N-[(5-phenyl-(3-pyridyl))methyl]carboxamide,hydroxy-N-[(5-phenyl(3-pyridyl))methyl]-amide,2-(phenyl-methylthio)pyridine, and benzylimidazole.

“Heteroarylheteroaryl” refers to a biaryl group where both of the arylgroups is a heteroaryl group. Exemplary heteroarylheteroaryl groupsinclude, for example, 3-pyridylimidazole, 2-imidazolylpyrazine, and thelike. Preferred optionally substituted heteroarylheteroaryl groupsinclude: 2-(4-piperazinyl-3-pyridyl)furan,diethyl-(3-pyrazin-2-yl(4-pyridyl))amine, and dimethyl{2-[2-(5-methylpyrazin-2-yl)ethynyl](4-pyridyl)}amine

“Optionally substituted” or “substituted” refers to the replacement ofhydrogen with a monovalent or divalent radical. Suitable substitutiongroups include, for example, hydroxyl, nitro, amino, imino, cyano, halo,thio, sulfonyl, thioamido, amidino, imidino, oxo, oxamidino,methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, alkyl,haloalkyl, alkyamino, haloalkylamino, alkoxy, haloalkoxy, alkoxy-alkyl,alkylcarbonyl, aminocarbonyl, arylcarbonyl, aralkylcarbonyl,heteroarylcarbonyl, heteroaralkyl-carbonyl, alkylthio, aminoalkyl,cyanoalkyl, aryl and the like.

The substitution group can itself be substituted. The group substitutedonto the substitution group can be carboxyl, halo, nitro, amino, cyano,hydroxyl, alkyl, alkoxy, aminocarbonyl, —SR, thioamido, —SO₃H, —SO₂R, orcycloalkyl, where R is typically hydrogen, hydroxyl or alkyl.

When the substituted substituent includes a straight chain group, thesubstitution can occur either within the chain (e.g., 2-hydroxypropyl,2-aminobutyl, and the like) or at the chain terminus (e.g.,2-hydroxyethyl, 3-cyanopropyl, and the like). Substituted substituentscan be straight chain, branched or cyclic arrangements of covalentlybonded carbon or heteroatoms.

“Carboxy-protecting group” refers to a carbonyl group which has beenesterified with one of the commonly used carboxylic acid protectingester groups employed to block or protect the carboxylic acid functionwhile reactions involving other functional sites of the compound arecarried out. In addition, a carboxy protecting group can be attached toa solid support whereby the compound remains connected to the solidsupport as the carboxylate until cleaved by hydrolytic methods torelease the corresponding free acid. Representative carboxy-protectinggroups include, for example, alkyl esters, secondary amides and thelike.

Certain of the compounds of the invention comprise asymmetricallysubstituted carbon atoms. Such asymmetrically substituted carbon atomscan result in the compounds of the invention comprising mixtures ofstereoisomers at a particular asymmetrically substituted carbon atom ora single stereoisomer. As a result, racemic mixtures, mixtures ofdiastereomers, as well as single diastereomers of the compounds of theinvention are included in the present invention. The terms “S” and “R”configuration, as used herein, are as defined by the IUPAC 1974“RECOMMENDATIONS FOR SECTION E, FUNDAMENTAL STEREOCHEMISTRY,” Pure Appl.Chem. 45:13-30, 1976. The terms α and β are employed for ring positionsof cyclic compounds. The α-side of the reference plane is that side onwhich the preferred substituent lies at the lower numbered position.Those substituents lying on the opposite side of the reference plane areassigned β descriptor. It should be noted that this usage differs fromthat for cyclic stereoparents, in which “α” means “below the plane” anddenotes absolute configuration. The terms α and β configuration, as usedherein, are as defined by the “Chemical Abstracts Index Guide,” AppendixIV, paragraph 203, 1987.

As used herein, the term “pharmaceutically acceptable salts” refers tothe nontoxic acid or alkaline earth metal salts of the compounds offormula (I). These salts can be prepared in situ during the finalisolation and purification of the compounds of formula (I), or byseparately reacting the base or acid functions with a suitable organicor inorganic acid or base, respectively. Representative salts include,but are not limited to, the following: acetate, adipate, alginate,citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,camphorate, camphorsulfonate, digluconate, cyclopentanepropionate,dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate,hemi-sulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-napth-alenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylproionate, picrate, pivalate, propionate,succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as alkyl halides, such as methyl, ethyl,propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates likedimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides suchas decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides,aralkyl halides like benzyl and phenethyl bromides, and others. Water oroil-soluble or dispersible products are thereby obtained.

Examples of acids that may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulfuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, methanesulfonic acid, succinic acidand citric acid. Basic addition salts can be prepared in situ during thefinal isolation and purification of the compounds of formula (I), orseparately by reacting carboxylic acid moieties with a suitable basesuch as the hydroxide, carbonate or bicarbonate of a pharmaceuticallyacceptable metal cation or with ammonia, or an organic primary,secondary or tertiary amine Pharmaceutically acceptable salts include,but are not limited to, cations based on the alkali and alkaline earthmetals, such as sodium, lithium, potassium, calcium, magnesium, aluminumsalts and the like, as well as nontoxic ammonium, quaternary ammonium,and amine cations, including, but not limited to ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, ethylamine, and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include diethylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine, and the like.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of theinvention. The term “prodrug” refers to compounds that are rapidlytransformed in vivo to yield the parent compound of the above formula,for example by hydrolysis in blood. A thorough discussion is provided inHiguchi, T., and V. Stella, “Pro-drugs as Novel Delivery Systems,”A.C.S. Symposium Series 14, and in “Bioreversible Carriers in DrugDesign,” in Edward B. Roche (ed.), American Pharmaceutical Association,Pergamon Press, 1987, both of which are incorporated herein byreference.

The term “cancer” refers to cancer diseases that can be beneficiallytreated by the inhibition of KSP, including, for example, solid cancers,such as carcinomas (e.g., of the lungs, pancreas, thyroid, bladder orcolon); myeloid disorders (e.g., myeloid leukemia); and adenomas (e.g.,villous colon adenoma). Cancer is a proliferative disease.

The compounds of the invention are useful in vitro or in vivo ininhibiting the growth of cancer cells. The compounds may be used aloneor in compositions together with a pharmaceutically acceptable carrieror excipient. Suitable pharmaceutically acceptable carriers orexcipients include, for example, processing agents and drug deliverymodifiers and enhancers, such as, for example, calcium phosphate,magnesium stearate, talc, monosaccharides, disaccharides, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,dextrose, hydroxypropyl-β-cyclodextrin, polyvinyl-pyrrolidinone, lowmelting waxes, ion exchange resins, and the like, as well ascombinations of any two or more thereof. Other suitable pharmaceuticallyacceptable excipients are described in “Remington's PharmaceuticalSciences,” Mack Pub. Co., New Jersey, 1991, incorporated herein byreference.

Effective amounts of the compounds of the invention generally includeany amount sufficient to detectably inhibit KSP activity by any of theassays described herein, by other KSP activity assays known to thosehaving ordinary skill in the art, or by detecting an inhibition oralleviation of symptoms of cancer.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. It will beunderstood, however, that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination, and the severity of the particular diseaseundergoing therapy. The therapeutically effective amount for a givensituation can be readily determined by routine experimentation and iswithin the skill and judgment of the ordinary clinician.

For purposes of the present invention, a therapeutically effective dosewill generally be a total daily dose administered to a host in single ordivided doses may be in amounts, for example, of from 0.001 to 1000mg/kg body weight daily and more preferred from 1.0 to 30 mg/kg bodyweight daily. Dosage unit compositions may contain such amounts ofsubmultiples thereof to make up the daily dose.

The compounds of the present invention may be administered orally,parenterally, sublingually, by aerosolization or inhalation spray,rectally, or topically in dosage unit formulations containingconventional nontoxic pharmaceutically acceptable carriers, adjuvants,and vehicles as desired. Topical administration may also involve the useof transdermal administration such as transdermal patches orionophoresis devices. The term parenteral as used herein includessubcutaneous injections, intravenous, intramuscular, intrasternalinjection, or infusion techniques.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-propanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordi-glycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols, which are solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as isnormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, cyclodextrins, and sweetening,flavoring, and perfuming agents.

The compounds of the present invention can also be administered in theform of liposomes. As is known in the art, liposomes are generallyderived from phospholipids or other lipid substances. Liposomes areformed by mono- or multi-lamellar hydrated liquid crystals that aredispersed in an aqueous medium. Any non-toxic, physiologicallyacceptable and metabolizable lipid capable of forming liposomes can beused. The present compositions in liposome form can contain, in additionto a compound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andphosphatidyl cholines (lecithins), both natural and synthetic. Methodsto form liposomes are known in the art. See, for example, Prescott(ed.), “Methods in Cell Biology,” Volume XIV, Academic Press, New York,1976, p. 33 et seq.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more other agents used in the treatment of cancer. Representativeagents useful in combination with the compounds of the invention for thetreatment of cancer include, for example, irinotecan, topotecan,gemcitabine, gleevec, herceptin, 5-fluorouracil, leucovorin,carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vincaalkaloids, imatinib, anthracyclines, rituximab, trastuzumab,topoisomerase I inhibitors, as well as other cancer chemotherapeuticagents.

The above compounds to be employed in combination with the compounds ofthe invention will be used in therapeutic amounts as indicated in thePhysicians' Desk Reference (PDR) 47th Edition (1993), which isincorporated herein by reference, or such therapeutically useful amountsas would be known to one of ordinary skill in the art.

The compounds of the invention and the other anticancer agents can beadministered at the recommended maximum clinical dosage or at lowerdoses. Dosage levels of the active compounds in the compositions of theinvention may be varied so as to obtain a desired therapeutic responsedepending on the route of administration, severity of the disease andthe response of the patient. The combination can be administered asseparate compositions or as a single dosage form containing both agents.When administered as a combination, the therapeutic agents can beformulated as separate compositions, which are given at the same time ordifferent times, or the therapeutic agents, can be given as a singlecomposition.

Antiestrogens, such as tamoxifen, inhibit breast cancer growth throughinduction of cell cycle arrest, that requires the action of the cellcycle inhibitor p27Kip. Recently, it has been shown that activation ofthe Ras-Raf-MAP Kinase pathway alters the phosphorylation status ofp27Kip such that its inhibitory activity in arresting the cell cycle isattenuated, thereby contributing to antiestrogen resistance (Donovan, etal, J. Biol. Chem. 276:40888, 2001). As reported by Donovan et al,inhibition of MAPK signaling through treatment with MEK inhibitorchanged the phosphorylation status of p27 in hormone refactory breastcancer cell lines and in so doing restored hormone sensitivity.Accordingly, in one aspect, the compounds of formula (I) may be used inthe treatment of hormone dependent cancers, such as breast and prostatecancers, to reverse hormone resistance commonly seen in these cancerswith conventional anticancer agents.

In hematological cancers, such as chronic myelogenous leukemia (CML),chromosomal translocation is responsible for the constitutivelyactivated BCR-AB1 tyrosine kinase. The afflicted patients are responsiveto gleevec, a small molecule tyrosine kinase inhibitor, as a result ofinhibition of Ab1 kinase activity. However, many patients with advancedstage disease respond to gleevec initially, but then relapse later dueto resistance-conferring mutations in the Ab1 kinase domain. In vitrostudies have demonstrated that BCR-Av1 employs the Raf kinase pathway toelicit its effects. In addition, inhibiting more than one kinase in thesame pathway provides additional protection againstresistance-conferring mutations. Accordingly, in another aspect of theinvention, the compounds of formula (I) are used in combination with atleast one additional agent, such as gleevec, in the treatment ofhematological cancers, such as chronic myelogenous leukemia (CML), toreverse or prevent resistance to the at least one additional agent.

In another aspect of the invention, kits that include one or morecompounds of the invention are provided. Representative kits include acompound of formula (I) and a package insert or other labeling includingdirections for treating a cellular proliferative disease byadministering an KSP inhibitory amount of the compound.

The present invention will be understood more readily by reference tothe following examples, which are provided by way of illustration andare not intended to be limiting of the present invention.

EXAMPLES

Referring to the examples that follow, compounds of the presentinvention were synthesized using the methods described herein, or othermethods, which are well known in the art.

The compounds and/or intermediates were characterized by highperformance liquid chromatography (HPLC) using a Waters Milleniumchromatography system with a 2690 Separation Module (Milford, Mass.).The analytical columns were Alltima C-18 reversed phase, 4.6×250 mm fromAlltech (Deerfield, Ill.). A gradient elution was used, typicallystarting with 5% acetonitrile/95% water and progressing to 100%acetonitrile over a period of 40 minutes. All solvents contained 0.1%trifluoroacetic acid (TFA). Compounds were detected by ultraviolet light(UV) absorption at either 220 or 254 nm. HPLC solvents were from Burdickand Jackson (Muskegan, Mich.), or Fisher Scientific (Pittsburgh, Pa.).In some instances, purity was assessed by thin layer chromatography(TLC) using glass or plastic backed silica gel plates, such as, forexample, Baker-Flex Silica Gel 1B2-F flexible sheets. TLC results werereadily detected visually under ultraviolet light, or by employing wellknown iodine vapor and other various staining techniques.

Mass spectrometric analysis was performed on one of two LCMSinstruments: a Waters System (Alliance HT HPLC and a Micromass ZQ massspectrometer; Column. Eclipse XDB-C18, 2.1×50 mm; solvent system: 5-95%(or 35-95%, or 65-95% or 95-95%) acetonitrile in water with 0.05% TFA;flow rate 0.8 mL/min; molecular weight range 500-1500; cone Voltage 20V; column temperature 40° C.) or a Hewlett Packard System (Series 1100HPLC; Column. Eclipse XDB-C18, 2.1×50 mm; solvent system: 1-95%acetonitrile in water with 0.05% TFA; flow rate 0.4 mL/min; molecularweight range 150-850; cone Voltage 50 V; column temperature 30° C.). Allmasses were reported as those of the protonated parent ions.

GCMS analysis is performed on a Hewlett Packard instrument (HP6890Series gas chromatograph with a Mass Selective Detector 5973; injectorvolume: 1 μL; initial column temperature: 50° C.; final columntemperature: 250° C.; ramp time: 20 minutes; gas flow rate: 1 mL/min;column^(.) 5% phenyl methyl siloxane, Model No. HP 190915-443,dimensions: 30.0 m×25 m×0.25 m).

Nuclear magnetic resonance (NMR) analysis was performed on some of thecompounds with a Varian 300 MHz NMR (Palo Alto, Calif.). The spectralreference was either TMS or the known chemical shift of the solvent.Some compound samples were run at elevated temperatures (e.g., 75° C.)to promote increased sample solubility.

The purity of some of the invention compounds is assessed by elementalanalysis (Desert Analytics, Tucson, Ariz.)

Melting points are determined on a Laboratory Devices MeI-Temp apparatus(Holliston, Mass.).

Preparative separations were carried out using a Flash 40 chromatographysystem and KP-Sil, 60A (Biotage, Charlottesville, Va.), or by flashcolumn chromatography using silica gel (230-400 mesh) packing material,or by HPLC using a C-18 reversed phase column. Typical solvents employedfor the Flash 40 Biotage system and flash column chromatography weredichloromethane, methanol, ethyl acetate, hexane, acetone, aqueoushydroxyamine, and triethyl amine. Typical solvents employed for thereverse phase HPLC were varying concentrations of acetonitrile and waterwith 0.1% trifluoroacetic acid.

The following are abbreviations used in the examples:

-   -   AcOH: Acetic acid    -   aq: Aqueous    -   ATP: Adenosine triphosphate    -   9-BBN 9-Borabicyclo[3.3.1]nonane    -   Boc: tert-butoxycarbonyl    -   Celite Filter agent    -   DAP or Dap: Diaminopropionate    -   DCM: Dichloromethane    -   DEAD: Diethyl azodicarboxylate    -   DIEA: Diisopropylethylamine    -   DMAP 4-Dimethylaminopyridine    -   DME: 1,2-Dimethoxyethane    -   DMF: N,N-Dimethylformamide    -   DMSO: Dimethyl sulfoxide    -   DPPA: Diphenyl phosphoryl azide    -   Et₃N: Triethylamine    -   EDC: N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide    -   EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide    -   EtOAc: Ethyl acetate    -   EtOH: Ethanol    -   Fmoc: 9-Fluorenylmethoxycarbonyl    -   Gly-OH: Glycine    -   HATU: O-(7-Azabenzotriaazol-1-yl)-N,N,N′N′-tetramethyluronium        hexafluorophosphate    -   HBTU: 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate    -   Hex: Hexane    -   HOBt: Butyl alcohol    -   HOBT: 1-Hydroxybenzotriazole    -   HPLC: High pressure liquid chromatography    -   NIS N-Iodosuccinimide    -   IC₅₀ value: The concentration of an inhibitor that causes a 50%        reduction in a measured activity.    -   iPrOH: Isopropanol    -   LC/MS: Liquid chromatography/mass spectrometry    -   LRMS: Low resolution mass spectrometry    -   MeOH: Methanol    -   NaOMe: Sodium methoxide    -   nm: Nanometer    -   NMP: N-Methylpyrrolidone    -   PPA Polyphosphoric acid    -   PPh₃: Triphenyl phosphine    -   PTFE Polytetrafluoroethylene    -   RP-HPLC: Reversed-phase high-pressure liquid chromatography    -   RT: Room temperature    -   sat: Saturated    -   TEA: Triethylamine    -   TFA: Trifluoroacetic acid    -   THF: Tetrahydrofuran    -   Thr: Threonine    -   TLC: Thin layer chromatography    -   Trt-Br: Tert-butyl bromide

Nomenclature for the Example compounds was provided using ACD Nameversion 5.07 software (Nov. 14, 2001) available from Advanced ChemistryDevelopment, Inc. Some of the compounds and starting materials werenamed using standard IUPAC nomenclature.

It should be understood that the organic compounds according to theinvention may exhibit the phenomenon of tautomerism. As the chemicalstructures within this specification can only represent one of thepossible tautomeric forms, it should be understood that the inventionencompasses any tautomeric form of the drawn structure.

It is understood that the invention is not limited to the embodimentsset forth herein for illustration, but embraces all such forms thereofas come within the scope of the above disclosure.

Example 1 Synthesis ofN-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamideStep 1: 3-benzyl-7-chloro-2-methylquinazolin-4(3H)-one

2-Amino-4-chlorobenzoic acid (250 mg, 1 eq.) and N-benzylacetamide (261mg, 1.2 eq.) were dissolved in phosphorus oxychloride (2 ml). Thereaction was placed in the microwave for 10 minutes at 150° C. Thereaction was quenched by pouring the mixture into ice. The crude productwas extracted into ethyl acetate. The ethyl acetate layer was washedwith water, 10% aqueous sodium hydroxide, dried with magnesium sulfate,filtered, and concentrated to yield3-benzyl-7-chloro-2-methylquinazolin-4(3H)-one as an orange solid.

Step 2:2-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N,N-dimethyl-acetamide

3-Benzyl-7-chloro-2-methylquinazolin-4 (3H)-one (2 g, 1 eq.) wasdissolved in tetrahydrofuran (20 ml). The solution was cooled to −78° C.for 15 minutes. Lithium hexamethyl disilazide (LHMDS) was added slowlyand the mixture was stirred at −78° C. for 45 minutes. Dimethylcarbamylchloride was added and the mixture was stirred at −78° C. for 1 h. Thereaction was allowed to warm to room temperature and stirred for 3 h.The solvent was evaporated and the resulting solid was dissolved inethyl acetate. The ethyl acetate layer was washed with water, saturatedsodium bicarbonate, saturated sodium chloride, dried over magnesiumsulfate, filtered and concentrated. The crude product was purified byflash chromatography to give2-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N,N-dimethylacetamide(1.2 g) as a solid.

Step 3:2-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-bromo-N,N-dimethylacetamide

To a mixture2-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N,N-dimethylacetamide(1.1 g, 1 eq.) and sodium acetate (761 mg, 3 eq.) in acetic acid (15ml), was added bromine (158 ul, 1 eq.) and the reaction was stirred atroom temperature for 4 h. Water was added and the product extracted intoethyl acetate. The ethyl acetate layer was washed several times withwater, saturated sodium bicarbonate, saturated sodium chloride, driedover magnesium sulfate, filtered, and concentrated to give2-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-bromo-N,N-dimethylacetamide(1.44 g) as a yellow solid.

Step 4: tert-butyl3-{[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]amino}propylcarbamate

To a solution of2-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-bromo-N,N-dimethylacetamide(1.4 g, 1 eq.) in of N,N-dimethylformamide (10 ml), was addedN-Boc-1,3-diaminopropane (2.8 g, 5 eq.). The reaction was stirred atroom temperature for 4 h and then heated to 40° C. The mixture wasstirred at 40° C. overnight. Water and ethyl acetate were added to themixture. The organic layer was washed with saturated sodium bicarbonate,saturated sodium chloride, dried over magnesium sulfate, filtered, andconcentrated. The crude product was purified by flash chromatography togive tert-butyl3-{[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]amino}propylcarbamate(1 g) as a pale yellow solid.

Step 5: tert-butyl3-[[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl](4-methylbenzoyl)amino]propylcarbamate

To a solution of tert-butyl3-{[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]amino}propylcarbamate(500 mg, 1 eq.) in methylene chloride (5 ml), was added 4-methyl benzoylchloride (380 ul, 3 eq.) and triethylamine (660 ul, 5 eq.). The reactionmixture was stirred at room temperature overnight. The solvent wasevaporated and the crude product was dissolved in ethyl acetate. Ethylacetate layer was washed with water, saturated sodium carbonate,saturated sodium chloride, dried over magnesium sulfate, filtered, andevaporated to yield crude tert-butyl3-[[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl](4-methylbenzoyl)amino]propylcarbamate.

Step 6:N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide

To a solution of tert-butyl3-[[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl](4-methylbenzoyl)amino]propylcarbamate(500 mg), was added 20% solution of trifluoroacetic acid in methylenechloride at room temperature. The mixture was stirred at roomtemperature overnight. The solvent was removed under reduced pressure.The crude product was purified by flash chromatography to giveN-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide(336 mg) as a white solid.

Example 2 Synthesis ofN-(3-aminopropyl)-N-[1-[7-chloro-3-(3-methylbenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamideStep 1:2-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N,N-dimethylacetamide

To a mixture of 2-amino-4-chloro methyl benzoate (5 g, 1 eq.) andN,N-dimethylamino acetamide (3.63 g, 1.2 eq.), was added a solution of4M HCl in dioxane (40 ml). The reaction was stirred at room temperatureovernight. Dioxane was removed at reduced pressure and the resultingsolid residue was triturated with cold water. The aqueous solution wasbasified with 10% ammonium hydroxide. The precipitate was collected,washed with more cold water, washed with ether and dried to yield2-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N,N-dimethylacetamide 7.4g (96%) as a white solid.

Step 2:2-bromo-2-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N,N-dimethyl-acetamide

To a mixture of2-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N,N-dimethylacetamide andsodium acetate (930 mg, 3 eq.) in acetic acid (15 ml), was added bromine(190 ul, 1 eq.). The reaction mixture was stirred at room temperatureovernight. Water was added and the product was extracted into ethylacetate. The ethyl acetate layer was washed several times with water,saturated sodium bicarbonate, saturated sodium chloride, dried overmagnesium sulfate, filtered, and concentrated to give2-bromo-2-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N,N-dimethylacetamide(0.95 g) as a brown solid.

Step 3: tert-butyl3-{[1-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]amino}propylcarbamate

To a solution of2-bromo-2-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N,N-dimethylacetamide(950 mg, 1 eq.) in N,N-dimethylformamide (10 ml), was addedN-Boc-1,3-diaminopropane (2.4 g, 5 eq.). The reaction was stirred at 60°C. for 30 minutes. Water and ethyl acetate was added. Ethyl acetatelayerwas washed with saturated sodium bicarbonate, saturated sodium chloride,dried over magnesium sulfate, filtered, and concentrated to givetert-butyl3-{[1-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]amino}propylcarbamate(1.2 g) as a pale orange solid.

Step 4:2-[1-[{3-[(tert-butoxycarbonyl)amino]propyl}(4-methylbenzoyl)amino]-2-(dimethylamino)-2-oxoethyl]-7-chloro-3,4-dihydroquinazolin-4-yl4-methylbenzoate

To a solution of tert-butyl3-{[1-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]amino}propylcarbamate(1.2 g, 1 eq.) methylene chloride 920 ml) at 0° C., was added 4-methylbenzoyl chloride (1.1 ml, 3 eq.) and triethylamine (1.9 ml, 5 eq.). Thereaction was allowed to warm up to room temperature and stirred at roomtemperature overnight. The solvent was evaporated and the crude productwas dissolved in ethyl acetate. Ethyl acetate layer was washed withwater, saturated sodium carbonate, saturated sodium chloride, dried overmagnesium sulfate, filtered, and evaporated to yield2-[1-[{3-[(tert-butoxycarbonyl)amino]propyl}(4-methylbenzoyl)amino]-2-(dimethylamino)-2-oxoethyl]-7-chloro-3,4-dihydroquinazolin-4-yl4-methylbenzoate (2.3 g) as a brown oil.

Step 5: tert-butyl3-[[1-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethyl-amino)-2-oxoethyl](4-methylbenzoyl)amino]propylcarbamate

To a solution of2-[1-[{3-[(tert-butoxycarbonyl)amino]propyl}(4-methylbenzoyl)amino]-2-(dimethylamino)-2-oxoethyl]-7-chloro-3,4-dihydroquinazolin-4-yl4-methylbenzoate in a 1:1 mixture of tetrahydrofuran and water (20 ml),was added lithium hydroxide (284 mg, 2 eq.) at room temperature. Themixture was stirred at room temperature for 3 h. The reaction mixturewas acidified with 1M of aqueous hydrogen chloride to pH 6-7 and laterextracted into methylene chloride. The organic layer was washed withmore water, dried over magnesium sulfate, filtered and concentrated. Theproduct was purified by flash chromatography to give tert-butyl3-[[1-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl](4-methylbenzoyl)amino]-propylcarbamate(257 mg) as a yellow solid.

Step 6: tert-butyl3-[[1-[7-chloro-3-(3-methylbenzyl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl](4-methylbenzoyl)amino]-propylcarbamate

To a solution of tert-butyl3-[[1-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl](4-methylbenzoyl)amino]propylcarbamate(29 mg, 1 eq.) in dimethyl formamide (1 ml), was added 3-methylbenzylbromide (8 μl, 1.2 eq.) and potassium carbonate (22 mg, 3 eq.). Thereaction mixture was stirred at room temperature overnight. Water wasadded and the material was extracted into ethyl acetate. Ethyl acetatelayer was washed with water, saturated sodium carbonate, saturatedsodium chloride, dried over magnesium sulfate, filtered, and evaporated.The product was purified by flash chromatography to give tert-butyl3-[[1-[7-chloro-3-(3-methylbenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl](4-methylbenzoyl)amino]propylcarbamate.

Step 7:N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-methylbenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide

To a solution of tert-butyl3-[[1-[7-chloro-3-(3-methylbenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl](4-methylbenzoyl)amino]propyl-carbamate,was added 20% solution of trifluoroacetic acid in methylene chloride atroom temperature. The reaction mixture was stirred at room temperaturefor 2 h. The solvent was removed under reduced pressure. The crudeproduct was purified by reverse phase HPLC to giveN-(3-aminopropyl)-N-[1-[7-chloro-3-(3-methylbenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide(9 mg) as TFA salt.

Example 3 Representative Quinazolinone Compounds

Representative quinazolinone compound compounds of the invention areshown in Table 1. In Table 1, MH+ refers to the molecular ion observedby mass spectrometry.

TABLE 1 Representative Quinazolinone Compounds. Compound Structure MH+Name 1

458.0 ethyl (3-benzyl-7-chloro-4-oxo-3,4- dihydroquinazolin-2-yl){[3-(dimethylamino)propyl]amino}acetate 2

641.0 ethyl (3-benzyl-7-chloro-4-oxo-3,4- dihydroquinazolin-2-yl){(4-bromobenzoyl)[3- (dimethylamino)propyl]amino}acetate 3

669.0 ethyl 2-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-{(4- bromobenzoyl)[3-(dimethylamino)propyl]amino}butanoate 4

576.1 ethyl (3-benzyl-7-chloro-4-oxo-3,4- dihydroquinazolin-2-yl)[[3-(dimethylamino)propyl](4- methylbenzoyl)amino]acetate 5

641.0 ethyl (3-benzyl-7-chloro-4-oxo-3,4- dihydroquinazolin-2-yl){(3-bromobenzoyl)[3- (dimethylamino)propyl]amino}acetate 6

641.0 ethyl (3-benzyl-7-chloro-4-oxo-3,4- dihydroquinazolin-2-yl){(2-bromobenzoyl)[3- (dimethylamino)propyl]amino}acetate 7

548.1 ethyl [(3-aminopropyl)(4- methylbenzoyl)amino](3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)acetate 8

576.1 ethyl (3-benzyl-7-chloro-4-oxo-3,4- dihydroquinazolin-2-yl)[[3-(dimethylamino)propyl](3- methylbenzoyl)amino]acetate 9

576.1 ethyl (3-benzyl-7-chloro-4-oxo-3,4- dihydroquinazolin-2-yl)[[3-(dimethylamino)propyl](2- methylbenzoyl)amino]acetate 10

640.0 N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(ethylamino)-2- oxoethyl]-4-bromo-N-[3-(dimethylamino)propyl]benzamide 11

655.0 isopropyl (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl){(4- bromobenzoyl)[3-(dimethylamino)propyl]amino}acetate 12

590.1 isopropyl (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)[[3- (dimethylamino)propyl](4-methylbenzoyl)amino]acetate 13

626.9 isopropyl [(3-aminopropyl)(4-bromobenzoyl)amino](3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)acetate 14

562.1 isopropyl [(3-aminopropyl)(4-methylbenzoyl)amino](3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)acetate 15

640.0 N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(diethylamino)-2-oxoethyl]-4- bromobenzamide 16

575.1 N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(diethylamino)-2-oxoethyl]-4- methylbenzamide 17

638.0 N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-oxo-2-pyrrolidin-1-ylethyl]-4- bromobenzamide 18

593.5 N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-oxo-2-pyrrolidin-1-ylethyl]-4- chlorobenzamide 19

654.0 N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-morpholin-4-yl-2-oxoethyl]-4- bromobenzamide 20

609.5 N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2 morpholin-4-yl-2-oxoethyl]-4-chlorobenzamide 21

611.9 N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]-4- bromobenzamide 22

567.5 N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]-4- chlorobenzamide 23

573.1 N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-oxo-2-pyrrolidin-1-ylethyl]-4- methylbenzamide 24

547.1 N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]-4- methylbenzamide 25

626.0 N-(3-aminopropyl)-N-[1-[3-(2- bromobenzyl)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)- 2-oxoethyl]-4-methylbenzamide26

581.5 N-(3-aminopropyl)-N-[1-[7-chloro-3-(2- chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)- 2-oxoethyl]-4-methylbenzamide27

581.5 N-(3-aminopropyl)-N-[1-[7-chloro-3-(3- chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)- 2-oxoethyl]-4-methylbenzamide28

581.5 N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4- methylbenzamide 29

565.1 N-(3-aminopropyl)-N-[1-[7-chloro-3-(3- methylbenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)- 2-oxoethyl]-4-methylbenzamide30

631.1 N-(3-aminopropyl)-N-[1-{7-chloro-4-oxo-3-[4-(trifluoromethoxy)benzyl]-3,4-dihydroquinazolin-2-yl}-2-(dimethylamino)- 2-oxoethyl]-4-methylbenzamide31

581.5 N-(3-aminopropyl)-N-[1-[7-chloro-3-(4- chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)- 2-oxoethyl]-4-methylbenzamide32

616.0 N-(3-aminopropyl)-N-[1-[7-chloro-3-(2,5-dichlorobenzyl)-4-oxo-3,4- dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide 33

616.0 N-(3-aminopropyl)-N-[1-[7-chloro-3-(2,6-dichlorobenzyl)-4-oxo-3,4- dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide 34

577.1 N-(3-aminopropyl)-N-[1-[7-chloro-3-(3- methoxybenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)- 2-oxoethyl]-4-methylbenzamide35

597.1 N-(3-aminopropyl)-N-[1-[7-chloro-3-(2- naphthylmethyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)- 2-oxoethyl]-4-methylbenzamide36

615.1 N-(3-aminopropyl)-N-[1-{7-chloro-4-oxo-3-[3-(trifluoromethyl)benzyl]-3,4-dihydroquinazolin-2-yl}-2-(dimethylamino)- 2-oxoethyl]-4-methylbenzamide37

631.1 N-(3-aminopropyl)-N-[1-{7-chloro-4-oxo-3-[3-(trifluoromethoxy)benzyl]-3,4-dihydroquinazolin-2-yl}-2-(dimethylamino)- 2-oxoethyl]-4-methylbenzamide38

683.1 N-(3-aminopropyl)-N-[1-{3-[3,5-bis(trifluoromethyl)benzyl]-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl}-2- (dimethylamino)-2-oxoethyl]-4-methylbenzamide 39

563.1 N-(3-aminopropyl)-N-[1-[7-chloro-3-(3- hydroxybenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)- 2-oxoethyl]-4-methylbenzamide40

575.1 N-(3-aminopropyl)-N-[1-[7-chloro-3-(3,5-dimethylbenzyl)-4-oxo-3,4- dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide 41

623.2 N-(3-aminopropyl)-N-[1-[3-(1,1′-biphenyl-3-ylmethyl)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)- 2-oxoethyl]-4-methylbenzamide42

572.1 N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-cyanobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4- methylbenzamide 43

592.1 N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-nitrobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4- methylbenzamide 44

548.1 N-(3-aminopropyl)-N-[1-[7-chloro-4-oxo-3-(pyridin-4-ylmethyl)-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4- methylbenzamide 45

616.0 N-(3-aminopropyl)-N-[1-[7-chloro-3-(3,4-dichlorobenzyl)-4-oxo-3,4- dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide 46

561.1 N-(3-aminopropyl)-N-{1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-[ethyl(methyl)amino]-2-oxoethyl}-4- methylbenzamide 47

589.1 N-(3-aminopropyl)-N-{1-[7-chloro-3-(3,5-dimethylbenzyl)-4-oxo-3,4- dihydroquinazolin-2-yl]-2-[ethyl(methyl)amino]-2-oxoethyl}-4- methylbenzamide 48

591.1 N-(3-aminopropyl)-N-{1-[7-chloro-3-(3- methoxybenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2- [ethyl(methyl)amino]-2-oxoethyl}-4-methylbenzamide 49

583.0 N-(3-aminopropyl)-N-[1-[7-chloro-3-(3,5-difluorobenzyl)-4-oxo-3,4- dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide 50

582.5 N-(3-aminopropyl)-N-[1-{7-chloro-3-[(6-chloropyridin-2-yl)methyl]-4-oxo-3,4-dihydroquinazolin-2-yl}-2-(dimethylamino)- 2-oxoethyl]-4-methylbenzamide51

582.5 N-(3-aminopropyl)-N-[1-{7-chloro-3-[(2-chloropyridin-4-yl)methyl]-4-oxo-3,4-dihydroquinazolin-2-yl}-2-(dimethylamino)- 2-oxoethyl]-4-methylbenzamide52

598.1 N-(3-aminopropyl)-N-[1-[7-chloro-4-oxo-3-(quinolin-2-ylmethyl)-3,4- dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide

Using the procedure described in Example 4, the above compounds wereshown to have an KSP inhibitory activity at an IC₅₀ of less than about50 μM. Certain of the compounds have an IC₅₀ of less than about 1 μM,and certain others of the compounds have an IC₅₀ of less than about 100nM.

Example 4 Assay for Determining KSP Activity

In this example, a representative in vitro assay for determining KSPactivity is described.

Purified microtubules from bovine brain were purchased from CytoskeletonInc. The motor domain of human KSP (Eg5, KNSL1) was cloned and purifiedto a purity of greater than 95%. Biomol Green was purchased fromAffinity Research Products Ltd.

Microtubules and the KSP motor protein were diluted in assay buffer (20mM Tris-HCl, pH 7.5, 1 mM MgCl₂, 10 mM DTT and 0.25 mg/ml BSA) to aconcentration of 35 ug/ml for microtubules and 45 nM for KSP. Themicrotubule/KSP mixture was then pre-incubated at 37° C. for 10 min topromote the binding of KSP to microtubules. ATP was also diluted to aconcentration of 300 uM in the same assay buffer. To each well of thetesting plate (384 well plate) containing 1.25 uL of compounds in DMSOor DMSO only, 25 uL of ATP solution. To start the reaction, 25 uL ofmicrotubule/KSP solution was added to the ATP/compound mixture. Theplates were incubated at room temperature for 1 hr. At the end ofincubation period, 65 uL of Biomol Green was added to each well. Theplates were incubated for 5-10 min and then the absorbance at 630 nm wasdetermined Biomol Green reagent is a malachite green based dye thatdetects the release of inorganic phosphate. Developed color signal wasread using a Victor II reader. The concentration of each compound for50% inhibition (IC₅₀) was calculated by nonlinear regression usingeither XLFit for Excel or Prism data analysis software by GraphP adSoftware Inc.

While the preferred embodiment of the invention has been illustrated anddescribed, it will be appreciated that various changes can be madetherein without departing from the spirit and scope of the invention.

1. A compound having the formula:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orprodrug thereof, wherein X is O or S; R₁ is selected from the groupconsisting of (1) hydrogen, (2) substituted or unsubstituted alkyl, (3)substituted or unsubstituted alkenyl, (4) substituted or unsubstitutedalkynyl, (5) substituted or unsubstituted aryl, (6) substituted orunsubstituted heteroaryl, (7) substituted or unsubstituted heterocyclyl,(8) substituted or unsubstituted alkylsulfonyl, and (9) substituted orunsubstituted arylsulfonyl; R₂ is selected from the group consisting of(1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted orunsubstituted alkenyl, and (4) substituted or unsubstituted alkynyl; R₃is selected from the group consisting of (1) CO₂R₁₀, (2) COR₁₀, (3)CONR₁₁R₁₂, (4) S(O)_(m)R₁₃, and (5) SO₂NR₁₄R₁₅; or R₂ and R₃ takentogether with the carbon atom to which they are attached form a 3- to7-membered carbocyclic or heterocyclic ring; with the proviso that whenR₄ and R₅ are taken together to form a 5- to 12-membered heterocyclicring, R₃ is CONR₁₁R₁₂ or R₂ and R₃ taken together with the carbon atomto which they are attached form a 3- to 7-membered carbocyclic orheterocyclic ring; R₄ is selected from the group consisting of (1)hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted orunsubstituted alkenyl, (4) substituted or unsubstituted alkynyl, (5)substituted or unsubstituted aryl, (6) substituted or unsubstitutedheteroaryl, and (7) substituted or unsubstituted heterocyclyl; R₅ isselected from the group consisting of (1) hydrogen, (2) substituted orunsubstituted alkyl, (3) substituted or unsubstituted alkoxy, (4)substituted or unsubstituted aryl, (5) substituted or unsubstitutedheteroaryl, (6) substituted or unsubstituted heterocyclyl, (7) COR₁₇,(8) CO₂R₁₈, (9) CONR₁₉R₂₀, and (10) SO₂R₂₁; or R₄ and R₅ are takentogether with the nitrogen atom to which they are attached form aheteroaryl or heterocyclyl ring, wherein the heteroaryl ring containsone or two ring heteroatoms, wherein the heterocyclyl ring contains oneor two ring heteroatoms, and wherein the heteroaryl or heterocyclyl ringis optionally substituted with a halogen, alkyl, hydroxy, amino, cyano,alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkoxy,aryl, aryloxy, heteroaryl, arylalkyl, heterocycle, aminocarbonyl,carbonylamino, alkylcarbonyl, alkylcarboxy, alkylaminocarbonyl,alkylcarbonylamino, carbocycle, or heteroarylalkyl group; with theproviso that when R₄ and R₅ taken together with the nitrogen atom towhich they are attached form a 5-membered heterocyclic ring, theheterocyclic ring is not a 2,4-dioxo-3-oxazolidinyl ring, a2,5-dioxo-1-imidazolidinyl ring, or a 2,4,5-trioxo-1-imidazolidinylring; R₆, R₇, R₈, and R₉ are independently selected from the groupconsisting of (1) hydrogen, (2) halogen, (3) hydroxy, (4) nitro, (5)amino, (6) cyano, (7) alkoxy, (8) alkylthio, (9) methylenedioxy, (10)haloalkoxy, (11) CO₂R₁₀, (12) COR₁₀, (13) OR₁₀, (14) CONR₁₁R₁₂, (15)substituted or unsubstituted alkyl, (16) substituted or unsubstitutedaryl, (17) substituted or unsubstituted heteroaryl, (18) substituted orunsubstituted alkylamino, (19) substituted or unsubstituteddialkylamino, (20) substituted or unsubstituted alkylsulfonyl, (21)substituted or unsubstituted arylsulfonyl, (22) substituted orunsubstituted alkylcarboxy, (23) substituted or unsubstitutedcarboxamido, (24) substituted or unsubstituted carboxyamino, (25)substituted or unsubstituted aminocarboxy, (26) substituted orunsubstituted aminocarbonyl, and (27) substituted or unsubstitutedalkylsulfonamido; R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₇, R₁₈, R₁₉, R₂₀, andR₂₁ are independently selected from the group consisting of (1)hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted orunsubstituted alkenyl, (4) substituted or unsubstituted alkynyl, (5)substituted or unsubstituted aryl, (6) substituted or unsubstitutedheteroaryl, and (7) substituted or unsubstituted heterocyclyl; or R₁₁and R₁₂, R₁₄ and R₁₅, or R₁₉ and R₂₀ taken together form a 3- to7-membered carbocyclic or heterocyclic ring; and m=0, 1, or
 2. 2. Acompound of claim 1, wherein substituted alkyl comprises arylalkyl,heteroarylalkyl, heterocyclyalkyl, aminoalkyl, alkylaminoalkyl,dialkyaminoalkyl, or sulfonamidoalkyl.
 3. A compound of claim 1, whereinX is O.
 4. A compound of claim 1, wherein R₁ is substituted orunsubstituted arylalkyl.
 5. A compound of claim 4, wherein R₁ is benzyl.6. A compound of claim 4, wherein R₁ is substituted benzyl.
 7. Acompound of claim 6, wherein R₁ is a halo-substituted benzyl.
 8. Acompound of claim 7, wherein R₁ is 3-chlorobenzyl.
 9. A compound ofclaim 7, wherein R₁ is 3-fluorobenzyl.
 10. A compound of claim 7,wherein R₁ is 3-methoxybenzyl.
 11. A compound of claim 7, wherein R₁ is3-trifluoromethylbenzyl.
 12. A compound of claim 7, wherein R₁ is3-trifluoromethoxybenzyl.
 13. A compound of claim 6, wherein R₁ is3,5-dimethylbenzyl.
 14. A compound of claim 1, wherein R₁ is2-naphthylmethyl.
 15. A compound of claim 1, wherein R₂ is hydrogen andR₃ is CO₂R₁₀.
 16. A compound of claim 15, wherein R₁₀ is alkyl.
 17. Acompound of claim 1, wherein R₂ is hydrogen and R₃ is CONR₁₁R₁₂.
 18. Acompound of claim 17, wherein R₁₁ and R₁₂ are alkyl.
 19. A compound ofclaim 18, wherein R₁₁ and R₁₂ are methyl.
 20. A compound of claim 17,wherein R₁₁ and R₁₂ taken together with the nitrogen atom to which theyare attached from a 3- to 7-membered heterocyclic ring.
 21. A compoundof claim 1, wherein R₄ is amino-substituted alkyl.
 22. A compound ofclaim 21, wherein R₄ is 3-aminopropyl.
 23. A compound of claim 1,wherein R₅ is hydrogen, alkyl, aryl, or COR₁₇.
 24. A compound of claim23, wherein R₅ is COR₁₇.
 25. A compound of claim 24, wherein R₁₇ isaryl, arylalkyl, alkyl-substituted aryl, or halogen-substituted aryl.26. A compound of claim 25, wherein aryl is phenyl
 27. A compound ofclaim 1, wherein R₆, R₈, and R₉ are hydrogen.
 28. A compound of claim 1,wherein R₇ is a halogen.
 29. A compound of claim 1 selected from thegroup consisting of:ethyl(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl){(4-bromobenzoyl)[3-(dimethylamino)propyl]amino}acetate;ethyl[(3-aminopropyl)(4-methylbenzoyl)amino](3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)acetate;isopropyl(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)[[3-(dimethylamino)propyl](4-methylbenzoyl)amino]acetate;isopropyl[(3-aminopropyl)(4-bromobenzoyl)amino](3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)acetate; isopropyl[(3-aminopropyl)(4-methylbenzoyl)amino](3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)acetate;N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(diethylamino)-2-oxoethyl]-4-bromobenzamide;N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(diethylamino)-2-oxoethyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-oxo-2-pyrrolidin-1-ylethyl]-4-bromobenzamide;N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-oxo-2-pyrrolidin-1-ylethyl]-4-chlorobenzamide;N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-morpholin-4-yl-2-oxoethyl]-4-bromobenzamide;N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-morpholin-4-yl-2-oxoethyl]-4-chlorobenzamide;N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]-4-bromobenzamide;N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]-4-chlorobenzamide;N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-oxo-2-pyrrolidin-1-ylethyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-methylbenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[1-{7-chloro-4-oxo-3-[4-(trifluoromethoxy)benzyl]-3,4-dihydroquinazolin-2-yl}-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[1-[7-chloro-3-(4-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-methoxybenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[1-[7-chloro-3-(2-naphthylmethyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[1-{7-chloro-4-oxo-3-[3-(trifluoromethyl)benzyl]-3,4-dihydroquinazolin-2-yl}-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[1-{7-chloro-4-oxo-3-[3-(trifluoromethoxy)benzyl]-3,4-dihydroquinazolin-2-yl}-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-hydroxybenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[1-[7-chloro-3-(3,5-dimethylbenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[1-[3-(1,1′-biphenyl-3-ylmethyl)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-cyanobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-nitrobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[1-[7-chloro-3-(3,4-dichlorobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide;N-(3-aminopropyl)-N-{1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-[ethyl(methyl)amino]-2-oxoethyl}-4-methylbenzamide;N-(3-aminopropyl)-N-{1-[7-chloro-3-(3,5-dimethylbenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-[ethyl(methyl)amino]-2-oxoethyl}-4-methylbenzamide;N-(3-aminopropyl)-N-{1-[7-chloro-3-(3,5-dimethylbenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-[ethyl(methyl)amino]-2-oxoethyl}-4-methylbenzamide;N-(3-aminopropyl)-N-{1-[7-chloro-3-(3-methoxybenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-[ethyl(methyl)amino]-2-oxoethyl}-4-methylbenzamide;N-(3-aminopropyl)-N-[1-[7-chloro-3-(3,5-difluorobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[1-{7-chloro-3-[(6-chloropyridin-2-yl)methyl]-4-oxo-3,4-dihydroquinazolin-2-yl}-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[1-{7-chloro-3-[(2-chloropyridin-4-yl)methyl]-4-oxo-3,4-dihydroquinazolin-2-yl}-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide;andN-(3-aminopropyl)-N-[1-[7-chloro-4-oxo-3-(quinolin-2-ylmethyl)-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide.30. A composition, comprising a pharmaceutically acceptable carrier andan amount of a compound of claim 1 effective to inhibit KSP activity ina human or animal subject when administered thereto.
 31. The compositionof claim 30 further comprising at least one additional agent for thetreatment of cancer.
 32. The composition of claim 31, wherein the atleast one additional agent for the treatment of cancer is selected fromirinotecan, topotecan, gemcitabine, gleevec, herceptin, 5-fluorouracil,leucovorin, carboplatin, cisplatin, taxanes, tezacitabine,cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab,and trastuzumab.
 33. A method for treating a condition by modulation ofKSP protein activity comprising administering to a human or animalsubject in need of such treatment an effective amount of a compound ofclaim
 1. 34. The method of claim 33, wherein the compound has an 1050value of less than about 50 μM in a cell proliferation assay.
 35. Themethod of claim 33, wherein the condition is cancer.
 36. A method forinhibiting KSP activity in a human or animal subject, comprisingadministering to the human or animal subject a composition comprising anamount of a compound of claim 1 effective to inhibit KSP activity thehuman or animal subject.
 37. A method for treating a cancer disorder ina human or animal subject, comprising administering to the human oranimal subject a composition comprising an amount of a compound of claim1 effective to inhibit KSP activity the human or animal subject.
 38. Themethod of claim 37 further comprising administering to the human oranimal subject at least one additional agent for the treatment ofcancer.
 39. The method of claim 38, wherein the at least one additionalagent for the treatment of cancer is selected from irinotecan,topotecan, gemcitabine, gleevec, herceptin, 5-fluorouracil, leucovorin,carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vincaalkaloids, imatinib, anthracyclines, rituximab, and trastuzumab.
 40. Acompound of claim 1 for use in the treatment of cancer.